Stable extended release oral dosage composition

ABSTRACT

A film-coated extended release solid oral dosage composition containing a nasal decongestant, pseudoephedrine or salt thereof, e.g., pseudoephedrine sulfate in a core effective to provide a geometric maximum plasma concentration of pseudoephedrine of about 345 ng/mL to about 365 ng/mL at a time of about 7.60 hrs to about 8.40 hrs and having two or three film-coatings on the core, the second one containing an amount of the non-sedating antihistamine, desloratadine, effective to provide a geometric maximum plasma concentration of desloratadine of about 2.15 ng/mL to about 2.45 ng/mL at a time of about 4.0 hours to about 4.5 hours, and use of the composition for treating patients showing the signs and symptoms associated with allergic and/or inflammatory conditions of the skin and airway passages are disclosed.

BACKGROUND OF THE INVENTION

[0001] This invention relates to a film-coated extended release solidoral dosage composition containing a nasal decongestant, e.g.,pseudoephedrine in a controlled release core and a film outer coatingcontaining the non-sedating antihistamine, desloratadine. The solid oraldosage compositions of this invention are useful for treating patientsshowing the signs and symptoms associated with allergic and/orinflammatory conditions such as the common cold, as well as signs andsymptoms associated with allergic and/or inflammatory conditions of theskin or upper and lower airway passages such as allergic rhinitis,seasonal allergic rhinitis and nasal congestion. upper respiratorydiseases, allergic rhinitis and nasal congestion.

[0002] Desloratadine, also called descarbethoxyloratadine, is disclosedin U.S. Pat. No. 4,659,716 as a non-sedating antihistamine useful as ananti-allergy agent. U.S. Pat. No. 6,100,274 discloses compositionscontaining desloratadine. U.S. Pat. No. 5,595,997 discloses methods andcompositions for treating seasonal allergic rhinitis symptoms usingdesloratadine. Desloratadine, upon oral absorption, is hydroxylated atthe 3 position to produce the metabolite, 3-hydroxyldesloratadine.

[0003] U.S. Pat. Nos. 4,990,535 and 5,100,675 disclose a twice-a-daysustained release coated tablet wherein the tablet coating comprisesdescarbethoxyloratadine and a hydrophilic polymer and polyethyleneglycol, and the tablet core comprises acetaminophen, pseudoephedrine ora salt thereof, a swellable hydrophilic polymer and pharmaceuticallyacceptable excipients.

[0004] U.S. Pat. No. 5,314,697 discloses an extended release tabletcontaining matrix core comprising pseudoephedrine sulfate and a coatingcomprising loratadine.

[0005] None of the prior art discloses the once-a-day film-coated solidoral dosage composition of this invention.

[0006] The successful development of a formulation of adesloratadine-pseudoephedrine once-a-day product would be desirable, butwould require achieving a release rate profile for pseudoephedrinecomponent over an extended period in excess of twelve hours andpreferably at least 16 hours while maintaining delivery of an effectiveonce a day dose of desloratadine.

[0007] It would be desirable for increased patient compliance to have anextended release desloratadine-pseudoephedrine product effective andsafe when used on a once-a-day basis for the treatment, managementand/or mitigation of the signs and symptoms associated with the commoncold, as well as allergic and/or inflammatory conditions of the skin orupper and lower airway passages such as seasonal, allergic rhinitis andnasal congestion.

SUMMARY OF THE INVENTION

[0008] We have discovered a desloratadine-pseudoephedrine once-a-dayproduct which produces a release rate profile for pseudoephedrine overan extended period in excess of twelve hours and preferably at least 16hours while maintaining delivery of an effective once a day dose ofdesloratadine.

[0009] Thus, the present invention provides film-coated extended releasesolid oral dosage composition comprising (a) a core comprising aneffective amount of pseudoephedrine or pharmaceutically acceptable saltthereof, and (b) a film coating uniformly covering the core andcomprising an effective amount of desloratadine wherein the amount ofpseudoephedrine or pharmaceutically acceptable salt thereof is effectiveto produce a geometric maximum plasma concentration of pseudoephedrineof about 345 ng/mL to about 365 ng/mL at a time of about 7.60 hrs toabout 8.40 hrs and the amount of desloratadine is effective to produce ageometric maximum plasma concentration of desloratadine of about 2.10ng/mL to about 2.45 ng/mL at a time of about 4.0 hours to about 4.5hours after administration of a single dose of said composition.

[0010] Preferred embodiments of the film-coated extended release solidoral dosage composition of the present invention also produce ageometric maximum plasma concentration of 3-hydroxydesloratadine ofabout 0.75 ng/mL to about 1.15 ng/mL at a time of about 5.50 hours toabout 6.25 hours after administration of a single dose of saidcomposition.

[0011] More preferred embodiments of the film-coated extended releasesolid oral dosage composition of the present invention also produce ageometric maximum plasma concentration of desloratadine of about 2.10ng/mL to about 2.45 ng/mL at a time of about 4.0 hours to about 4.5hours and a geometric maximum plasma concentration of3-hydroxydesloratadine of about 0.75 ng/mL to about 1.15 ng/mL at a timeof about 5.50 hours to about 6.25 hours after administration of a singledose of said composition.

[0012] Thus, in a preferred embodiment, this invention provides apharmaceutical composition comprising therapeutically effective amountof pseudoephedrine sulfate in a core and an effective amount ofdesloratadine in a film coating maintaining the desirablepharmacokinetic parameters of desloratadine, 3-hydroxydesloratadine andpseudoephedrine listed herein above.

[0013] This invention also provides a film-coated extended release solidoral dosage composition comprising (a) a core comprising about 240 mg ofpseudoephedrine or pharmaceutically acceptable salt thereof, and (b) afilm coating uniformly covering the core and comprising about 5 mg ofdesloratadine wherein total desloratadine degration products in thefilm-coated extended release oral dosage composition is less than orequal to about 2.0 weight percent. Preferably, total desloratadinedegradation products in the film-coated extended release solid oraldosage composition is less than or equal to 1.0 to about 1.5 weightpercent, and more preferably is less than or equal to 0.8 to about 1.0weight percent, after storage of the compositions at 25 C and 60%relative humidity for at least about 24 months.

[0014] The major desloratadine degradation products in the film-coatedextended release solid oral dosage composition are (1)N-methyl-desloratadine, and (2) N-formyldesloratadine. See Chart.

[0015] This invention also provides a film-coated extended release solidoral dosage composition comprising (a) a core comprising about 240 ofpseudoephedrine or pharmaceutically acceptable salt thereof, and (b) afirst film coating uniformly covering the core; and (c) a second filmcoating uniformly covering the first coating comprising about 5 mg ofdesloratadine; wherein more than about 90% of the desloratadine in solidoral dosage composition dissolves into a stirred 0.1N HCl solution at37° C. in about 45 minutes, and more than about 90% of thepseudoephedrine sulfate in solid oral dosage composition dissolves intoa stirred 0.1N HCl solution at 37° C. (1^(st) hour) and thereafter in astirred phosphate buffer having a pH of 7.5 at 37° C. over 16 hours.

[0016] This invention also provides a film-coated extended release solidoral dosage composition comprising (a) a core comprising an effectiveamount of pseudoephedrine or pharmaceutically acceptable salt thereof,and (b) a film coating uniformly covering the core and comprising aneffective amount of desloratadine wherein the amount of pseudoephedrineor pharmaceutically acceptable salt thereof is effective to produce ageometric mean steady state maximum plasma concentration ofpseudoephedrine of about 382 ng/mL to about 664 ng/mL at a time of about5.25 hrs to about 7.99 hrs after administration of a daily dose of saidcomposition for at least about 10 consecutive days and the amount ofdesloratadine is effective to produce a geometric mean steady statemaximum plasma concentration of desloratadine of about about 1.59 ng/mLto about 3.39 ng/mL at a time of about about 2.24 hours to about 5.12hours after administration of a daily dose of said composition for atleast about 12 consecutive days.

[0017] Preferred embodiments of the film-coated extended release solidoral dosage composition of the present invention also produce ageometric mean steady state maximum plasma concentration ofpseudoephedrine is about 418 ng/mL to about 628 ng/mL at a time of about5.32 hrs to about 7.98 hrs after administration of a daily dose of saidcomposition for at least about 10 consecutive days and the geometricmean steady state maximum plasma concentration of desloratadine is aboutabout 1.95 ng/mL to about 2.93 ng/mL at a time of about 2.94 hours toabout 4.42 hours after administration of a daily dose of saidcomposition for at least about 12 consecutive days.

[0018] Preferred embodiments of the film-coated extended release solidoral dosage composition of the present invention also produce ageometric mean steady state maximum plasma concentration of3-hydroxy-desloratadine of about 1.25 ng/mL to about 1.87 ng/mL at atime of about 3.44 hours to about 5.86 hours and a geometric mean steadystate value for the area under the plasma concentration-time curve from0-24 hours for 3-hydroxy-desloratadine was about 20.3 ng hr/mL to about3.11 ng hr/mL after administration of a daily dose of said compositionfor at least about 12 consecutive days.

[0019] Preferred embodiments of the film-coated extended release solidoral dosage composition of the present invention also produce ageometric mean steady state value for the area under the plasmaconcentration-time curve from 0 to 24 hours for desloratadine was about23.0 ng hr/mL to about 46.6 ng hr/mL.

[0020] Preferred embodiments of the film-coated extended release solidoral dosage composition of the present invention also produce ageometric mean steady state value for the area under the plasmaconcentration-time curve from 0 to 24 hours for desloratadine was about27.8 ng hr/mL to about 41.8 ng hr/mL.

[0021] Preferred embodiments of the film-coated extended release solidoral dosage composition of the present invention also produce ageometric mean steady state value for the area under the plasmaconcentration-time curve from 0 to 24 hours for pseudo-ephedrine wasabout 6244 ng hr/mL to about 11346 ng hr/mL.

[0022] Preferred embodiments of the film-coated extended release solidoral dosage composition of the present invention also produce ageometric mean steady state value for the area under the plasmaconcentration-time curve from 0 to 24 hours for pseudoephedrine wasabout 7030 ng hr/mL to about 10554 ng hr/mL.

[0023] The present invention also provides a film-coated extendedrelease solid oral dosage composition comprising (a) a core comprisingan effective amount of pseudoephedrine or pharmaceutically acceptablesalt thereof, and (b) a film coating uniformly covering the core andcomprising an effective amount of desloratadine, wherein the amount ofpseudoephedrine or pharmaceutically acceptable salt thereof is effectiveto produce a geometric mean steady state minimum plasma concentration ofpseudoephedrine of about 82 ng/mL to about 243 ng/mL afteradministration of a daily dose of said composition for at least about 10consecutive days and the amount of desloratadine is effective to producea geometric mean steady state minimum plasma concentration ofdesloratadine of about 0.307 ng/mL to about 1.095 ng/mL afteradministration of a daily dose of said composition for at least about 12consecutive days.

[0024] Preferred embodiments of the film-coated extended release solidoral dosage composition of the present invention also produce ageometric mean steady state minimum plasma concentration ofpseudoephedrine is about 129 ng/mL to about 193 ng/mL afteradministration of a daily dose of said composition for at least about 10consecutive days and the geometric mean steady state minimum plasmaconcentration of desloratadine is about 0.624 ng/mL to about 0.946 ng/mLafter administration of a daily dose of said composition for at leastabout 12 consecutive days.

[0025] Preferred embodiments of the film-coated extended release solidoral dosage composition of the present invention also produce ageometric mean steady state miniimum plasma concentration of3-hydroxy-desloratadine of about 0.503 ng/mL to about 0.875 ng/mL afteradministration of a daily dose of said composition for at least about 12consecutive days.

[0026] Preferred embodiments of the film-coated extended release solidoral dosage composition of the present invention also produce ageometric mean steady state miniimum plasma concentration of3-hydroxy-desloratadine of about 0.551 ng/mL to about 0.827 ng/mL afteradministration of a daily dose of said composition for at least about 12consecutive days.

[0027] We have also discovered that by placing a first coating betweenfilm-coating comprising desloratadine and the core comprising a nasaldecongestant, e.g., pseudoephedrine salt, preferably pseudoephedrinesulfate, provides release of desloratadine from the second film-coatingand extended release of the nasal decongestant pseudoephedrine sulfatefrom the core, preferably a matrix core, over a period in excess oftwelve hours while maintaining the desirable pharmacokinetic parametersof desloratadine, 3-hydroxydesloratadine and pseudoephedrine listedherein above and wherein the total desloratadine degradation productsproduced is less than or equal 2.0 weight percent, preferably is lessthan or equal 1.0 to about 1.5 weight percent, and more preferably isless than or equal to 0.8 to about 1.0 weight percent, after storage ofthe compositions at 25 C. and 60% relative humidity for at least about24 months.

[0028] Thus, in a preferred embodiment, the present invention provides afilm-coated extended release solid oral dosage composition comprising:

[0029] (a). a matrix core comprising:

[0030] 1. an extended release amount of a pharmaceutically acceptabledecongestant;

[0031] 2. a polymer matrix;

[0032] 3. a water insoluble basic calcium, magnesium or aluminum salt;

[0033] 4. a binder;

[0034] 5. a lubricant; and optionally,

[0035] 6. a glidant;

[0036] (b) a first film coating uniformly covering the matrix corecomprising;

[0037] 1. a water-swellable film-forming neutral or cationic copolymericester;

[0038] 2. a lubricant;

[0039] 3. a film-modifier; and

[0040] 4. optionally, an anti-foaming agent;

[0041] (c) a second film coating uniformly covering the first coating,comprising:

[0042] 1. an immediate release amount of desloratadine;

[0043] 2. a water-swellable film-forming neutral or cationic copolymericester;

[0044] 3. a lubricant;

[0045] 4. a water soluble film-modifier; and optionally,

[0046] 5. an anti-foaming agent;

[0047] The film-coated extended release solid oral dosage compositionsof the present invention release at least about 80%, and preferably atleast about 90% of the desloratadine into a 0.1N HCl solution at 37° C.within about 45 minutes and at least about 50% of the pseudoephedrinesulfate dissolves into a stirred 0.1N HCl solution at 37° C. (1^(st)hour) and thereafter in a stirred phosphate buffer having a pH of 7.5 at37° C. in 5 hours. and at least about 80% of the pseudoephedrine sulfatedissolves into the stirred solution in 10 hours and at least about 93%of the pseudoephedrine sulfate dissolves into the stirred solution in 16hours.

[0048] In another preferred embodiment, the present invention provides afilm-coated extended release solid oral dosage composition comprising:(a) a matrix core comprising: Ingredient mg/core Pseudoephedrine Sulfateabout 240 Hydroxypropyl Methylcellulose 2208 100,000 cps. about 160-480Ethylcellulose about 40-120 Dibasic Calcium Phosphate Dihydrate about56-162 Povidone about 20-60 Silicon Dioxide about 6-12 MagnesiumStearate about 2-6 Approximate Matrix Core Weigh Range: about 518-1082mg

[0049] and

[0050] (b) a first film coating uniformly covering the matrix corecomprising:

[0051] (1) a neutral copolymer of ethyl acrylate and methyl acrylate;

[0052] (2) a lubricant selected from talc, silicon dioxide and magnesiumstearate;

[0053] (3) a polyethylene glycol selected form polyethylene glycol 200to polyethylene glycol 8000; and

[0054] (4) optionally, a pharmaceutically acceptable mixture ofhomologous liquid methyl siloxane polymers and silica gel; and

[0055] (c) a second film coating uniformly coating the first coating,comprising:

[0056] (1) an amount of desloratadine effective to produce a geometricmaximum plasma concentration of desloratadine of about 2.10 ng/mL toabout 2.45 ng/mL at a time of about 4.0 hours to about 4.5 hours afteradministration of a single dose of said composition;

[0057] (2) a neutral copolymer of ethyl acrylate and methyl acrylate;

[0058] (3) a lubricant selected from talc, silicon dioxide and magnesiumstearate;

[0059] (4) a polyethylene glycol selected from polyethylene glycol 200to polyethylene glycol 8000; and optionally

[0060] (5) a pharmaceutically acceptable mixture of homologous liquidmethyl siloxane polymers and silica gel.

[0061] The above-listed preferred film-coated extended solid oral dosagecomposition may further comprise a third film coating uniformly coveringthe second film coating, wherein the third film coating comprises:

[0062] (1) a neutral copolymer of ethyl acrylate and methyl acrylate;

[0063] (2) a lubricant selected from talc, silicon dioxide and magnesiumstearate;

[0064] (3) an effective amount of at least one a water-solublefilm-modifying agent selected from low viscosity hydroxypropylcellulose, methyl hydroxyethyl cellulose and sodium carboxymethylcellulose, and a polyethylene glycol selected from polyethylene glycol200 to polyethylene glycol 8000 or mixtures thereof;

[0065] (4) a pharmaceutically acceptable dye; and

[0066] (5) optionally a pharmaceutically acceptable mixture ofhomologous liquid methyl siloxane polymers and silica gel.

[0067] In a more preferred embodiment, the present invention provides afilm-coated extended release solid oral dosage composition comprising:(a) a matrix core comprising: Ingredient mg/core Pseudoephedrine Sulfateabout 240 Hydroxypropyl Methylcellulose 2208 about 160-480 100,000 cps.Ethylcellulose about 40-120 Dibasic Calcium Phosphate Dihydrate about54-162 Povidone about 20-60 Silicon Dioxide about 6-12 MagnesiumStearate about 2-6 Approximate (Matrix Core) Weight about 518-1082 mgRange: (b) a first film coating uniform by covering the matrix corecomprising: Ingredient mg/first coating (d) a neutral copolymer of ethylacrylate about 1.36-about 4.08 and methyl acrylate having an averagemolecular weight of 800,000; (2) a lubricant selected from talc, siliconabout 1.36-about 4.08 dioxide and magnesium stearate; (3) a polyethyleneglycol selected from a about 0.136-about 0.408 polyethylene glycol 6000to a polyethylene glycol 8000 and (4) optionally, a pharmaceuticallyabout 0.11-about 0.33 acceptable mixture of homologous liquid methylsiloxane polymers and silica gel; Total for first film coating: about2.96-8.89 mg and (c) a second film coating uniformly coating the firstcoating, said second film comprising: Ingredient mg/second film coating(1) a 24-hour amount of desloratadine; about 5.0-about 6.0 (2) a neutralcopolymer of ethyl about 3.04-about 9.12 acrylate and methyl acrylatehaving an average molecular weight of 800,000; (3) a lubricant selectedfrom talc, about 3.5-about 10.5 silicon dioxide and magnesium stearate;(4) a polyethylene glycol selected from about 0.915-about 2.75 apolyethylene glycol 6000 to a polyethylene glycol 8000; and (5)optionally, a pharmaceutically about 0.14-about 042 acceptable mixtureof homologous liquid methyl silsoxane polymers and silica gel; Total forsecond coating: about 12.60-about 38.79 mg

[0068] In a preferred embodiment, the present invention provides afilm-coated extended release oral dosage composition comprising:

[0069] a. a matrix core comprising: Ingredient mg/core PseudoephedrineSulfate about 240 Hydroxypropyl Methylcellulose 2208 about 160-480100,000 cps. Ethylcellulose about 40-120 Dibasic Calcium Phosphate about56-162 Povidone about 20-60 Silicon Dioxide; and about 6-12 MagnesiumStearate about 2-6 Approximate Matrix Core Weight Range: about 518-1082mg

[0070] (b) a first film coating uniform by covering the matrix corecomprising:

[0071] (1) a neutral copolymer of ethyl acrylate and methyl acrylatehaving molecular weight of 800,000;

[0072] (2) a lubricant selected from talc, silicon dioxide and magnesiumstearate;

[0073] (3) a polyethylene glycol selected from a polyethylene glycol 200to polyethylene glycol 8000; and

[0074] (4) optionally a pharmaceutically acceptable mixture ofhomologous liquid methyl siloxane polymers and silica gel; and

[0075] (c) a second film coating uniformly covering the first coatingcomprising:

[0076] (1) an amount of desloratadine effective to produce a geometricmaximum plasma concentration of desloratadine of about 2.10 ng/mL toabout 2.45 ng/mL at a time of about 4.0 hours to about 4.5 hours afteradministration of a single dose of said composition;

[0077] (2) a netural copolymer of ethyl acrylate and methyl acrylatehaving an average molecular weight of 800,000;

[0078] (3) a lubricant selected from talc, silicon dioxide and magnesiumstearate;

[0079] (4) a polyethylene glycol selected from a polyethylene glycol 200to a-polyethylene 8000; and

[0080] (5) optionally a pharmaceutically acceptable mixture of homogousliquid methyl siloxane and polymers and silica gel.

[0081] A more preferred composition of the present invention is providedherein below: 1. Matrix Core Ingredient mg/core Pseudoephedrine SulfateUSP 240 Hydroxypropyl Methylcellulose 2208 USP 320 100,000 cpsEthylcellulose NF Type 7 80 Dibasic Calcium Phosphate USP Dihydrate 108Povidone USP 40 Silicon Dioxide NF 8 Magnesium Stearate NF 4 ApproximateMatrix Core Weight: 800 mg 1. Matrix Core Coatings 1. First FilmCoating: Ingredient mg/tablet Simethicone 0.22 Polyethylene glycol 80000.27 Talc NF 2.72 Ethyl Acrytalc/Methyl Methacrylate neutral copolymer2.72 (30% dispersion in water) Subtotal for first coating 5.93 mg 2.Second Film (Immediate Release) Coating mg/tablet Desloratadine 6.0Simethicone 0.28 Polyethylene glycol 8000 1.83 Talc NF 5.88 EthylAcrylate/Methyl methacrylate neutral copolymer 6.09 Subtotal for secondcoating 20.08 mg 3. Third Film Coating mg/tablet HydroxypropylMethylcellulose 2910 USP 6 cps 2.09 Talc NF 5.79 Ethyl Acrylate/MethylMethacrylate Neutral 4.18 copolymer Polyethylene Glycol 8000 NF 0.42Simethicone 0.11 Spectra Spray Med Blue Dye 3.65 Subtotal for thirdcoating: 16.24 mg Approximate Total of Three Coatings Weight: 42.37 mgApproximate Tablet (MatrixCore and Three Coatings) 842.97 mg Weight:

[0082] Another more preferred composition of the present invention isprovided herein below: 1. Matrix Core Ingredient mg/core PseudoephedrineSulfate USP 240 Hydroxypropyl Methylcellulose 2208 USP 320 100,000 cpsEthylcellulose NF Type 7 80 Dibasic Calcium Phosphate USP Dihydrate 108Povidone USP 40 Silicon Dioxide NF 8 Magnesium Stearate NF 4 ApproximateMatrix Core Weight: 800 mg 2. Matrix Core Coatings 1. First FilmCoating: Ingredient mg/tablet Simethicone 0.22 Polyethylene glycol 80000.27 Talc NF 2.72 Ethyl Acrytalc/Methyl Methacrylate neutral copolymer2.72 (30% dispersion in water) Subtotal for first coating: 5.93 mg 2.Second Film (Immediate Release) Coating mg/tablet Desloratadine 5.0Simethicone 0.28 Polyethylene glycol 8000 0.61 Talc NF 5.17 EthylAcrylate/Methyl methacrylate neutral copolymer 6.09 HydroxypropylMethylcellulose 2910 USP 6 cps 3.05 Subtotal for second coating: 20.20mg 3. Third Film Coating mg/tablet Hydroxypropyl Methylcellulose 2910USP 6 cps 2.09 Talc NF 5.79 Ethyl Acrylate/Methyl Methacrylate Neutral4.18 copolymer Polyethylene Glycol 8000 NF 0.42 Simethicone 0.11 SpectraSpray Med Blue Dye 3.65 Subtotal for third coating 16.24 mg ApproximateTotal of Three Coatings Weight: 42.37 mg Approximate Tablet (MatrixCore& Three Coatings) 842.37 mg Weight:

[0083] Similar results would be expected if a decongestant effectiveamount of another pharmaceutically acceptable pseudoephedrine salt,e.g., pseudo-ephedrine hydrogen chloride was used in place ofpseudoephedrine sulfate.

[0084] The compositions of the present invention are useful fortreatment of allergic and/or inflammatory conditions of the skin (e.g.urticaria) and the upper and lower airway passages including the nasaland non-nasal symptoms of seasonal allergic rhinitis including nasalcongestion in patients in need of such treating.

DETAILED DESCRIPTION OF THE INVENTION

[0085] During the course of development of the compositions of thepresent invention, desloratadine was found to be unstable and todiscolor when stored in combination with various excipients such asthose disclosed in U.S. Pat. No. 5,314,697 as part of the matrix corecontaining pseudoephedrine sulfate. The excipients causing discolorationand instability of desloratadine include acidic excipients having a pHof less than 7 in water such as organic acids, such as stearic acid,povidone, crospovidone and carbonyl-containing materials such aslactose, and ethyl cellulose and hydroxylpropyl methylcellulose. Binderslike povidone and polymers such as hydroxypropymethylcellulose areuseful as a polymer matrix for the sustained release of thepseudoephedrine sulfate from the inner polymer matrix core.

[0086] We discovered that by uniformly covering the inner core matrixcontaining a nasal decongestant, e.g., pseudoephedrine sulfate andhydroxypropyl methylcellulose, ethyl cellulose and povidone with a firstcoating comprising a water-swellable film-forming neutral or cationiccopolymeric ester, a film modifier and lubricant, the desloratadinecould safely be coated onto the first coating. The desloratadine wasfound to have an acceptable immediate release profile from the secondcoating (about 80%, and preferably at least about 90% of thedesloratadine is released in 0.1N HCl in less than about 45 min.) andtotal desloratadine degradation products in the film-coated extendedrelease solid oral dosage composition is less than or equal to 1.0 toabout 1.5 weight percent, and more preferably is less than or equal to0.8 to about 1.0 weight percent, after storage for at least 24 months at25° C. and about 60% relative humidity (“RH”).

[0087] When a third film coating comprising a water swellablefilm-forming neutral or cationic co-polymeric ester and polyethyleneglycol as a film modifier was placed on top of the second coating, thedissolution rate of desloratadine from the second coating andpseudoephedrine from the core decreased to unacceptably low levels.

[0088] Surprisingly, addition of a low viscosity hydroxylpropylmethylcellulose to the third coating as a film-modifier, restored thedissolution rates of both active ingredients (pseudoephedrine sulfateand desloratadine) to levels approximately the same as those obtainedwhen a core matrix was uniformly covered with two film coatings.

[0089] The phrase “allergic and inflammatory conditions of the skin andairway passages” is meant those allergic and inflammatory conditions andsymptoms found on the skin and in the upper and lower airway passagesfrom the nose to the lungs. Typical allergic and inflammatory conditionsof the skin and upper and lower airway passages include seasonal andperennial allergic rhinitis, non-allergic rhinitis, asthma includingallergic and non-allergic asthma, sinusitis, colds (in combination witha NSAID, e.g., aspirin, ibuprofen or acetaminophen) and/or adecongestant e.g. pseudoephedrine), dermatitis, especially allergic andatopic dermatitis, and urticaria and symptomatic dermographism as wellas retinophathy, and small vessel diseases, associated with diabetesmellitus.

[0090] The amount of desloratadine effective for treating or preventingallergic and inflammatory conditions of the skin and upper and lowerairway passages will vary with the age, sex, body weight and severity ofthe allergic and inflammatory condition of the patient. Typically, theamount of desloratadine effective for treating or preventing suchallergic and inflammatory conditions is in the range of about 2.5 mg/dayto about 60 mg/day, preferably about 2.5 mg/day to about 20 mg/day, orabout 4.0 mg/day to about 15 mg/day, or about 5.0 mg/day to about 10mg/day, more preferably about 5.0 mg/day to about 10.0 mg/day, and mostpreferably about 5.0 mg/day to about 6.0 mg/day in a single dose.

[0091] Desloratadine is a non-sedating long acting histamine antagonistwith potent selective peripheral H1-receptor antagonist activity.Following oral administration, loratadine is rapidly metabolized todescarboethoxyloratadie or desloratadine, a pharmacologically activemetabolite. In vitro and in vivo animal pharmacology studies have beenconducted to assess various pharmacodynamic effects of desloratadine andloratadine. In assessing antihistamine activity in mice (comparison ofED₅₀ value), desloratadine was relatively free of producing alterationsin behavior alterations in behavior, neurologic or autonomic function.The potential for desloratadine or loratadine to occupy brainH1-receptors was assessed in guinea pigs following i.p. administrationand results suggest poor access to central histamine receptors fordesloratadine or loratadine.

[0092] In addition to antihistaminic activity, desloratadine hasdemonstrated anti-allergic and anti-inflammatory activity from numerousin vitro and in vivo tests. These in vitro tests (mainly conducted oncells of human origin) have shown that desloratadine can inhibit manyevents in the cascade of allergic inflammation. These anti-inflammatoryeffects for desloratadine are independent of the H1-antagonist effect ofdesloratadine and include: The release of inflammatory mediatorshistamine, truptase, leukotriene and prostaglandin D2 from mast cells;

[0093] The release of inflammatory cytokines including IL-4, IL-6, IL-8and IL-13; The release of the inflammatory chemokines such as RANTES(regulated upon activation, normal T cell expressed and presumablysecreted); Superoxide anion production of polymorphonuclear neutrophils;The expression of cell adhesion molecules such as intracellular adhesionmolecules (ICAM-1) and P-selection in endothelial cells; and Eosinophilmigration and adhesion. In vivo studies also suggest that an inhibitoryeffect of desloratadine on allergic bronchospasm and cough can also beexpected.

[0094] The clinical efficacy and safety of desloratadine has beendocumented in over 3,200 seasonal allergic rhinitis patients in 4double-blind, randomized clinical trials The results of these chemicalstudies demonstrated the efficacy of desloratadine in the treatment ofadult and adolescent patients with seasonal rhinitis.

[0095] The nasal decongestants useful in the present invention includephenylpropanolamine, phenylephrine and and pseudoephedrine.Pseudoephedrine as well as pharmaceutically acceptable acid additionalsalts, e.g., those of HCl or H₂SO₄, is a sympathomimetic drug recognizedby those skilled in the art as a safe therapeutic agent effective fortreating nasal congestion and is commonly administered orally andconcomitantly with an antihistamine for treatment of nasal congestionassociated with allergic rhinitis. The use of pseudoephedrine as a nasaldecongestant in the present invention is preferred; the use ofpseudoephedrine sulfate is more preferred.

[0096] In the course of development of the oral dosage composition ofthis invention, it was discovered that the selection of the polymers forthe polymer matrix core was critical to achieve the desired extendedrelease period of at least 12 hours, preferably 12 to 16 hours and morepreferably for at least 16 hours for pseudoephedrine sulfate. Forexample, the use of hydroxypropyl methyl cellulose 4,000 cps or 15,000cps as polymers in the matrix core did not provide this more preferredextended release period of at least 16 hours for dose of pseudoephedrinesulfate. We discovered that only by selecting for inclusion into thematrix core of specific weight ratios of three specific polymers was thedesired pseudoephedrine release profile achieved. Only by combining (1)four parts by weight of hydroxypropyl methyl cellulose 2208 USP, 100,000cps with (2) one part by weight of ethyl cellulose together with (3) 1/2part by weight of povidone as a secondary binder was the more preferredextended release profile of at least 16 hours for pseudoephedrinesulfate from the matrix core achieved. The matrix core also containsspecific amounts of silicon dioxide as a glidant and magnesium stearateas a lubricant. The tablet hardness 22±6 Strong-Cobb Units (SCU) is notgreatly affected by the higher level of lubricant (6 mg/tablet) but itis preferred to maintain the lubricant level at 1/10 part by weight oflubricant to one part by weight of povidone as secondary binder.

[0097] The term “lubricant” as used herein refers to a substance addedto the dosage form to enable the dosage form, e.g., a tablet, after ithas been compressed to releases from the mold or die.

[0098] Suitable lubricants include talc, magnesium stearate, calciumstearate, stearic acid, hydrogenated vegetable oils and the like.Preferably, magnesium stearate or talc is used.

[0099] The term “glidants” as used herein refers to a substance, such asan anti-caking agent, which improves the flow characteristics of apowder mixture.

[0100] Suitable glidants include silicon dioxide and talc. Preferably,silicon dioxide is used.

[0101] The term “binders” as used herein means any material that isadded to pharmaceutical compositions to help hold such compositionstogether and release the medicament therefrom.

[0102] Suitable binders are selected from the group consisting of:croscarmellose sodium, a cross-linked polymer of carboxymethylcellulosesodium, povidone, crospovidone, starches, celluloses, alginates, andgums; see also USP XXII page 1858 (1990). Preferably, povidone is used.

[0103] Typically suitable antifoaming agents include mixtures ofhomologous liquid methylsiloxane and silica gel available under theSimethecone tradename.

[0104] The term “water-swellable film-forming neutral or cationiccopolymeric ester,” as used herein means neutral and cationic copolymersof ethyl acrylate and substituted unsubstituted methyl or ethylmethacrylate esters.

[0105] Typically suitable water swellable film-forming neutralcopolymeric esters include neutral copolymers of ethyl acrylate andmethyl metharylate such as are available from Pharma Poloymers, acompany of the Hüls Group under the EUDRAGIT® Tradename; EUDRAGIT NE30D.and Kollicoat available from BASF, Mt Olive, N.J. An aqueous dispersioncontaining 30% by weight of a neutral copolymer based on ethyl crylateand methyl methoacrylate (average molecular weight of approximately800,000) is preferred.

[0106] Typically suitable water-swellable film-forming cationicco-polymeric esters include cationic co-polymerers based ondimethylaminoethylmethacrylate and a neutral methacrylic ester such asthe EUDRAGIT E copolymers available from Pharma Polymers as a 12.5%solution (EUDRAGIT E 12.5) or as solid (EUDRAGIT E 100) and quaternayammonium copolymers described in USP/NF as “Amononio methacrylatecopolymer, Type A” and Type “B”. Such copolymers are available asaqueous dispersions of copolymers of acrylic and methacrylic acid esterswith a low (substitution) content of quaternary ammonium groups presentas salts, (e.g., quaternary ammonium chlorides). Type A and Type B areavailable as 30% aqueous dispersions under the EUDRAGIT RL 30D andEUDRAGIT RS 30D tradenames, respectively. Use of the water-swellablefilm-from neutral co-polymeric esters based on ethyl acrylate andmethacrylate is preferred.

[0107] The term “water soluble film modifier” as used herein means afilm-forming agent which modifies the water-swellable characteristics ofthe film-forming neutral or cationic copolymeric esters useful in thecompositions of the present invention. A typically suitable watersoluble film-modifying agent is a low viscosity (≦20 cps) cellulose suchas low viscosity hydroxypropyl methyl cellulose, low viscosityhydroxylethyl methyl cellulose; low viscosity sodium carboxymethylcellulose or a polyethylene glycol selected from polyethylene glycol 200to polyethylene glycol 8000.

[0108] Use of a polyethylene glycol 6000 to polyethylene glycol 8000 asa film modifier is preferred in the first and second coatings; the useof polyethylene glycol 8000 in each coating is more preferred.

[0109] Use of polyethylene glycol in combination with a low viscosityhydroxypropyl methylcellulose in the third coating is preferred. Use ofa mixture of polyethylene glycol 8000 and hydroxypropyl methylcellulose2910 cps in the third or outermost film coating is more preferred.

[0110] The term “water insoluble basic calcium, magnesium and aluminiumsalts” as used herein means the pharmaceutically acceptable carbonates,phosphates, silicates and sulfates of calcium, magnesium and aluminum ormixtures thereof. Typically suitable pharmaceutically acceptable basicsalts include calcium sulfate anhydrous, hydrates of calcium sulfate,such as calcium sulfate dihydrate, magnesium sulfate anhydrous, hydratesof magnesium sulfate, dibasic calcium phosphate, dibasic calciumsilicate, magnesium trisilicate, magnesium phosphate, aluminum silicate,and hydrates of magnesium phosphate, aluminum phosphate; and calciumphosphate is more preferred. The use of dibasic calcium phosphatedihydrate is most preferred.

[0111] The hydroxylpropyl methylcellulose 2910 acts as a film-formingagent in the film coating, and the polyethylene glycols act as filmmodifier. Other suitable film-forming polymers which may be used includelow viscosity (720 cps) hydroxypropyl celluloses, methyl hydroxyethylcellulose and sodium carboxymethyl cellulose.

[0112] The oral dosage composition of this invention also provides ashelf life of more than 24 months, e.g., up to 36 and 48 months so longas the tablets are stored in standard package at between 2° and 30° C.in an ambient environment of 60% relative humidity.

[0113] In the preparation of the tablet core, the povidone is dissolvedin a mixture of alcohol and water. The pseudoephedrine sulfate,hydroxypropyl methylcellulose 2208 USP, 100,000 cps, ethylcellulose, anddibasic calcium phosphate are blended and granulated with an alcoholicwater solution containing povidone. The granulation is milled, and driedto a loss on drying between 0.5 to 2.0%.

[0114] The dried granulation is milled and blended with requisiteamounts of silicon dioxide and magnesium stearate. The final blend iscompressed to produce the inner polymer matrix core composition.

[0115] The coatings are normally applied to the inner polymer matrixcores in the following manner:

[0116] Cores are charged into a suitable coating pan. A water dispersionof talc, Simethicone, polyethylene glycol 8000 and EUDRAGIT NE30D isapplied to the matrix cores as a first coating. These coated matrixcores are then coated with a dispersion of desloratadine, Simethicone,EUDRAGIT NE 30D, polyethylene glycol 8000 NF and talc dispersion. Thisis followed by an application of third coating containing a dispersionof FD & C Blue No. 2 Aluminum lake containing EDTA as a chelating agent,talc, Simethicone, EUDRAGIT NE30D, containing hydroxy-propylmethylcellulose 2910 cps. and polyethylene glycol 8000 NF. The coatedtablets are then branded (with black ink) and packaged in plasticbottles and blisters for storage at a temperature between 2° C. and 30°C. in an ambient environment During the course of development of theformulations of the present invention, we discovered that the in vitrodissolution studies showed a decrease in both the desloratadine releaserate and in desloratadine concentration at increased pH, especially pHvalues >7.0, compared to those for a 5 mg tablet of desloratadine. Thein vivo studies showed the Tmax was greater than 4 hours and that asignificant part of the absorptive desloratadine process occurs in thesmall intestine which has an alkaline pH (pH values>7.0).

[0117] We discovered we could increase the release of desloratadine byincreasing the level of hydroxypropyl methylcellulose and lowering thelevels of the plasticizing agent, e.g., polyethylene glycol 8000, and ofthe lubricant, e.g., talc, in the second film coating containingdesloratadine. See Example 4.

[0118] In another preferred embodiment, the effective amount ofdesloratadine in the second film coating was increased to 6.0 mg andamount of talc was reduced (by about 1.12 mg) to produce an acceptablepharmacokinetic profile. See Example 3 and Table 3.

[0119] For the solid oral dosage formulations of the present invention,the geometric mean maximum plasma concentration of pseudoephedrine (PES)is about 345 ng/mL to about 365 ng/mL at a time (Tmax) of about 7.60hours to about 8.40 hours; the geometric mean maximum plasma concentrateof desloratadine (DL) is about 2.10 ng/mL to about 2.45 ng/mL,preferably 2.15 ng/mL to about 2.35 ng/mL at a time (Tmax), of about 4.0hours to about 4.5 hours and the geometric mean maximum plasmaconcentrate of 3-hydroxydesloratadine (3-OH-DL) is about 0.75 ng/mL toabout 1.15 ng/mL, preferably about 0.85 ng/mL to about 1.05 ng/mL, andmore preferably preferably about 0.88 ng/mL to about 1.02 ng/mL at atime (Tmax) of about 5.50 hours to about 6.25 hours after administrationof a single dose of said composition to healthy subjects.

Pharmacokinetic Study No. 1

[0120] The pharmacokinetic objective of this study was to determine thebioavailability and bioequivalence of desloratadine (DL), 3-OH DL andpseudoephedrine(PES) from the formulation of Example 2 (5 mg of DL/240mg of PES) of this application relative to that of a 5 mg of Example 11of U.S. Pat. No. 6,100,274 (USP '274) and an extended-releasepseudoephedrine core as references. This study was a Phase 1,open-label, single-dose, randomized, three-way crossover study with aseven-day washout period between each treatment. Thirty-six healthy maleand female subjects received each of the following treatments in theorder assigned by a computer-generated random code: Treatment A: One 5mg DL/240 mg PES tablet of Example 2. Treatment B: One DL 5 mg tablet ofExample 11 of USP.′274. Treatment C: One 240 mg pseudoephedrine sulphate(oval extended- release pseudoephedrine cores from Claritin ® D-24coated with placebo Claritin ® D-24 coat).

[0121] The tablets were administered with 180 mL (6 fluid ounces) ofnon-carbonated room temperature water. The tablet was swallowed whole,not chewed or crushed. After dosing, the oral cavity was inspected toassure that the subject had swallowed the tablet. Subjects continuedfasting until the four-hour study procedures were complete. Water waspermitted throughout the fasting period, except for two hours post-dose.The subjects remained awake and seated upright/ambulatory for four hourspost-dose. All subjects were confined to the study site until the120-hour blood samples, vital signs and laboratory tests were obtained.

[0122] Serial blood samples (10 mL) were to be collected into tubescontaining heparin as an anticoagulant at the following time points: 0(pre-dose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 36, 48,48, 72, 96 and 120 hours post-dose. No food was allowed for four hoursafter dosing. Drinking water was not allowed from one hour pre-dose toone hour postdose, except for the 120 mL administered with thetreatment. Plasma concentrations of pseudoephedrine were determinedusing a validated liquid chromatography with tandem mass spectrometric(LC/MS/MS) method with a lower limit of quantitation (LOQ) of 10.0ng/mL, and a linear range of 10.0-400 ng/mL. The associated meanpharmacokinetic parameters are provided in Table 1.

[0123] The mean DL Cmax following administration of DL tablet of Example2 of the present invention or a 5 mg desloratadine tablet of Example 11of U.S. Pat. 6,100,274 were 1.79 and 2.23 ng/mL, respectively, and werereached at mean Tmax values of 6.78 and 5.10 hours, respectively. TABLE1 Mean (% CV^(a)) Pharmacokinetic Parameters of DL, and 3-OH DL inHealthy Subjects Following Single-Dose Oral Administration of DL D-24and DL DL Example 2- Example 11 of 5 mg/240 mg USP′274-5 mg (TreatmentA) (Treatment B) Parameter (units) Mean % CV Mean % CV Cmax (ng/mL) 1.7935.8 2.23 34.8 Tmax (hr) 6.78 57.3 5.10 52.5 3-OH DL Example 2- Example11 of D-24 5 mg/240 mg USP′274-5 mg (Treatment A) (Treatment B)Parameter (units) Mean % CV Mean % CV Cmax (ng/mL) 0.695 59.4 0.832 55.2Tmax (hr) 6.09^(b) 32.7 4.96^(b) 31.4

[0124] The mean 3-OH DL Cmax following administration of 5 mgDL/240mgPES tablet of Example 2 of this application and a 5 mg desloratadinetablet of Example 11 of U.S. Pat. No. 6,100,274 were 0.695 and 0.832ng/mL, respectively, and were reached at mean Tmax values of 6.09 and4.96 hours, respectively. The peak plasma concentration of 3-OH DLdecreased slowly with half-life of 29.6 hours following administrationof 5 mgDL/240 mgPES tablet of Example 2 of this application, and 29.5hours following administration of the 5 mg DL tablet of U.S. Pat. No.6,100,274.

[0125] Statistical comparisons of Cmax and AUC(tf) followingadministration of tablet of Example 2 of this application and 5 mgdesloratadine tablet of U.S. Pat. No. 6,100,274 were performed for DKand 3-OH DL plasma concentrations.

[0126] The results showed that the 90% confidence intervals for DL and3-OH DL did not meet the 80-125% bioequivalence guidelines for both Cmaxand AUC(tf). For those subjects where AUC(I) could be determined, theconfidence intervals of DL for AUC(I) did not meet the 80-125bioequivancy guidelines. However, the confidence intervals of 3-OH DLfor AUC(I) did meet the 80-125 bioequivances guidelines.

[0127] The mean pharmacokinetic parameters of pseudoephedrine areprovided in Table 2. TABLE 2 Mean (% CV^(a)) Pharmacokinetic Parametersof Pseudoephedrine in Healthy Subjects Following Single-Dose OralAdministration of DL D-24 and 240 mg Pseudoephedrine Sulphate (OvalExtended- Release Pseudoephedrine Cores from Claritin ® D-24 Coated withPlacebo Claritin ® D-24 Coat) Tablets (n = 36) PseudoephedrinePseudoephedrine Sulphate (Oval- Extended Release 5 mg/240 mg TabletPseudoephedrine of Example 2 Cores from of this application ClaritinD-24) Mean % CV Mean % CV Cmax (ng/mL) 328  25 349 18.1 Tmax (hr) 8.42 34 7.36 36.3 AUC (tf) (ng-hr/mL) 6438  42 6225 38.5 tf (hr) 44.0  3740.0 25.8 AUC (l) (ng-hr/mL) 6780  40 6452 37.3 t½ (hr) 10.3 148 7.2521.6

[0128] The mean pseudoephedriine Cmax following administration of the (5mg DL/240 mgPES) tablet of Example 2 or a 240 mg pseudoephedrinesulphate extended-release core were 328 and 349 ng/mL, respectively.Statistical comparisons of Cmax and AUC(tf) values for DL D-24 (5 mg/240mg) versus 240 mg pseudoephedrine sulphate (extended-release core) wereperformed. The power to detect a 20% difference in treatment means at ana-level of 0.05 (two-tailed) for the log-transformed Cmax and AUC(tf)were 100 and 93%, respectively.

[0129] The 90% confidence intervals for pseudoephedrine met the 80-125%bioequivalence guidelines for both Cmax and AUC(tf). For those subjectswere AUC(I) could be determined, the confidence intervals for AUC(I)also met the 80-125 guidelines.

Pharmacokinetic Study No. 2

[0130] Subjects were confined at the study site at least 12 hours priorto each treatment (Day—1). In the morning of Day 1, following a ten-hourovernight fast, each subject received one of the following treatmentsbased on his/her subject number and the study period:

[0131] Treatment A: One (5 mg DL/240 mgPES) tablet of Example 2 of thisapplication

[0132] Treatment B: One (6 mgDL/240 mgPES) tablet of Example 3 of thisapplication

[0133] Treatment C: One 5 mg DL tablet of Example 11 of USP' 274 plusone 120 mg PES tablet (oval extended-release pseudoephedrine core).

[0134] The study procedures, blood collection times and the analyticalmethodologies summarized in Study No. 1 were employed.

[0135] The mean pharmacokiinetic parameters are shown in Table 3. Thepower to detect a 20% difference in treatment means of DL at an cc-levelof 0.05 (two tailed) for the log-transformed AUC(tf), AUC(I), and Cmaxvalues were 89%, 90% and 88% respectively. TABLE 3 Mean (% CV¹)Pharmacokinetic Parameters of DL, 3-OH DL and Pseudoephedrine in HealthyAdult Volunteers (n = 42) Following Single-Dose Oral Administration ofDl Tablets of Examples 2 (5 mg DL/240 mgPES), Example 3 (6 mg DL/240 mgPES) or a 5 mg DL Tablet of USP′274 Plus One 240 mg PES Tablet.Treatment Cmax (ng/mL) % CV Tmax (hr)/ % CV DL A²  1.91 44 4.69 52 B³ 2.35 43 4.33 50 C⁴  2.28 40 3.87 67 3-OH DL A²  0.77 28 6.67 52 B³ 1.00 39 6.12 48 C⁴  0.93 31 5.68 58 Pseudoephedrine A² 353   30 7.71 45B³ 362   28 8.14 46 C⁴ 349   22 8.31 47

[0136] The results show that, based on plasma 3-OH DL concentrations,the (5 mg/240 mg) of Example 2 is not equivalent to the 5 mg DL tabletof Example 11 of USP '274 and that the 6 mgDL/240 PESmg of Example 3 and5 mg DL tablet of Example II of USP', 274 are bioequivalent.

[0137] The results show that, the bioequivalence of pseudoephedrine fromthe formulations of Examples 2 & 3 was established relative to thereference product.

Pharmacokinetic Study No. 3

[0138] Forty health volunteers were enrolled in this open label,randomized, three-way cross-over, single-dose study. The subjects wererandomized to receive, following a ten hour over-night fast: TreatmentA: 5 mg DL/240 mg PES of Example 4 of this appln Treatment B: DL 5 mg ofExample 11 of USP ′274 Plus 240 mg PES

[0139] The procedures of Study No. 1 were followed using theabove-listed treatments.

[0140] The mean pharmacokinetic parameters for DL, 3-OH DL andpseudoephedrine are provided in Table 4. TABLE 4 Mean (% CV¹)Pharmacokiinetic Parameters of DL, 3-OH DL and Pseudoephedrine inHealthy Adult Volunteers (n = 40) Following Single-Dose OralAdministration of One 5 mg D-24 Tablet of Example 4 or One 5 mg DLTablet of USP′274 Plus One 240 mg Pseudoephedrine Sulfate TabletTreatment Cmax (ng/mL) % CV Tmax (hr) % CV DL A²  2.15 41 4.13 66 B³ 2.30 44 4.83 62 3-OH DL A²  0.89 48 5.60 42 B²  1.07 36 6.10 37Pseudoephedrine A² 382   34 7.83 29 B² 399   32 8.43 36

Pharmacokinetic Study No. 4

[0141] The pharmacokinetic objective of this study was to determine thepharmacokinetic profile of desloratadine (DL), 3-OH DL andpseudoephedrine(PES) following daily administration of the formulationof Example 5 (5 mg of DL/240 mg of PES) of this application for 14consecutive days. This study was a Phase 1, open-label, multiple-dosestudy for 14 consecutive days. Eighteen healthy male and female subjectswere enrolled and 17 completed the study; one discontinued. One 5 mgDL/240 mg PES tablet of Example 5. Was administered in the morning(approximately 8 AM).

[0142] The tablets were administered with 180 mL (6 fluid ounces) ofnon-carbonated room temperature water. The tablet was swallowed whole,not chewed or crushed. After dosing, the oral cavity was inspected toassure that the subject had swallowed the tablet. Subjects continuedfasting until the four-hour study procedures were complete. Water waspermitted throughout the fasting period, except for two hours post-dose.The subjects remained awake and seated upright/ambulatory for four hourspost-dose. All subjects were confined to the study site until the120-hour blood samples, vital signs and laboratory tests were obtained.

[0143] Serial blood samples (10 mL) were to be collected into tubescontaining heparin as an anticoagulant at the following time points: 0(pre-dose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 36, 48,48, 72, 96 and 120 hours post-dose. No food was allowed for four hoursafter dosing. Drinking water was not allowed from one hour pre-dose toone hour postdose, except for the 120 mL administered with thetreatment. Plasma concentrations of DL, 3-OH DL and pseudoephedrine weredetermined using a validated liquid chromatography with tandem massspectrometric (LC/MS/MS) method with a lower limit of quantitation (LOQ)of 0.025 ng/mL, 0.025 ng/mL,and 10.0 ng/mL, respectively. The Themethods were validated over concentration range of 0.025 ng/mL-10.0-400ng/mL for DL, 0.025 ng/mL-10.0-400 ng/mL for 3-OH DL, and 10.0-400 ng/mLfor pseudoephedrine,. The associated mean steady state pharmacokineticparameters are provided in Tables 5 & 6. TABLE 5 Mean (% CV^(a)) SteadyState Pharmacokinetic Parameters of DL, 3-OH DL and Pseudoephedrine inHealthy Subjects Following Multiple- Dose Oral Administration of DL D-24For 14 Consecutive Days AUC(0-24 h) Cmax(ng/mL) Tmax(hr) Cavg(ng/mL)(ng-hr/mL) Mean % CV Mean % CV Mean % CV Mean % CV DL 2.44 35 3.68 391.45 34 34.8 34 3-OH DL 1.56 20 4.65 26 1.07 21 25.7 21 Pseudoephedrine523 27 6.65 21 366 29 8795 29

[0144] The mean steady state DL Cmax following daily administration ofDL tablet of Example 5 of the present invention for 14 consecutive dayswas 2.44 ng/mL, and was reached at mean Tmax value of 3.68 hours. Themean steady state DL Cavg following administration of tablet was 1.45ng/mL. The mean steady state AUC(0-24h) following administration of thetablet was 34.8 ng.hr/mL. The mean 3-OH DL Cmax following administrationof 5 mgDL/240 mgPES tablet of Example 5 of this application was 1.56ng/mL, and was reached at mean Tmax value 4.65 hour. The mean steadystate 3-OH DL Cavg was 1.07 ng/mL. The mean steady state AUC(0-24 h)following administration of the tablet was 25.7 ng.hr/mL.

[0145] For the solid oral dosage formulations of the present invention,the geometric mean maximum plasma concentration of pseudoephedrine (PES)is about 382 ng/mL to about 664 ng/mL at a time (Tmax) of about 5.25hours to about 7.99 hours; preferably, about 418 ng/mL to about 628ng/mL at a time (Tmax) of about 5.32 hours to about 7.98, and ageometric mean steady state value for the area under the plasmaconcentration-time curve from 0-24 hours for pseudoephedrine was about6244 ng hr/mL to about 11346 ng hr/mL, preferably, was about 7030 nghr/mL to about 10554 ng/mL, after administration of a multiple dose ofsaid composition to healthy subjects for at least 10 consecutive days(steady state attained after 10, days data measured over the 14 days),and the geometric mean maximum plasma concentrate of desloratadine (DL)is about 1.59 ng/mL to about 3.39 ng/mL at a time (Tmax) of about 2.24hours to about 5.12, preferably, 1.95 ng/mL to about 2.93 ng/mL at atime (Tmax), of about 2.94 hours to about 4.42 hours, and a geometricmean steady state value for the area under the plasma concentration-timecurve from 0-24 hours for desloratadine was about 23.0 ng hr/mL to about46.6 ng hr/mL, preferably, was about 27.8 ng hr/mL to about 41.8 nghr/mL,after administration of a multiple dose of said composition tohealthy subjects for at least 12 consecutive days (steady state attainedafter 12 days data measured over the 14 days), and the geometric meanmaximum plasma concentrate of 3-hydroxydesloratadine (3-OH-DL) is about1.25 ng/mL to about 1.87 ng/mL at a time (Tmax) of about 3.44 hours toabout 5.86 hours, and a geometric mean steady state value for the areaunder the plasma concentration-time curve from 0-24 hours for3-hydroxy-desloratadine was about 20.3 ng hr/mL to about 3.11 ng hr/mLafter administration of a multiple dose of said composition to healthysubjects for at least 12 consecutive days (steady state attained after12 days, data measured over the 14 days).

[0146] The mean trough concentrations of DL, 3-OH DL, and ofpseudoephedrine are provided in Table 6. TABLE 6 Mean (% CV^(a))Pharmacokinetic Parameters of Pseudoephedrine in Healthy SubjectsFollowing Multiple-Dose Oral Administration of DL D-24 (n = 17) For 14Consecutive Days Cmin (ng/ml) Percent Fluctuation Mean % CV Mean % CVDL)  0.788 39 115   14 3-OH DL  0.689 27  82.9 18 Pseudoephedrine 161   51 102   22

[0147] The steady state conditions for DL and 3-OH DL were attained onDay 12 following daily administration of DL as indicated by a lack of astatistically significant difference (p>0.301) in the mean trough plasmaconcentrations of DL between mean trough plasma concentration of DL Dayand that on Day 14. The steady state mean trough plasma concentrationfor pseudoephedrine was attained on Day 10.

[0148] For the solid oral dosage formulations of the present invention,the geometric mean minimum plasma concentration of pseudoephedrine (PES)is about 82 ng/mL to about 243 ng/mL, and preferably, about 129 ng/mL toabout 193 ng/mL after administration of a multiple dose of saidcomposition to healthy subjects for at least 10 consecutive days (steadystate attained after 10 days,data measured over the 14 days), and thegeometric mean minimum plasma concentrate of desloratadine (DL) is about0.307 ng/mL to about 1.095 ng/mL, preferably, 0.624 ng/mL to about 0.946ng/mL, after administration of a multiple dose of said composition tohealthy subjects for at least 12 consecutive days (steady state attainedafter 12 days, data measured over the 14 days),and the geometric meanminimum plasma concentrate of 3-hydroxydesloratadine (3-OH-DL) is about0.503 ng/mL to about 0.875 ng/mL, and preferably about 0.551 ng/mL toabout 0.827 ng/mL after administration of a multiple dose of saidcomposition to healthy subjects for at least 12 consecutive days (steadystate attained after 12 days, data measured over the 14 days).

EXAMPLE 1

[0149] This example illustrates preparation of the preferred oral dosagecomposition of this invention. The ingredients and specific amountsthereof are listed below.

[0150] 1. Matrix Core

[0151] A. Method of Manufacture:

[0152] 1. Dissolve povidone in a mixture of 3 parts of alcohol and 1part of purified water.

[0153] 2. Combine the pseudoephedrine sulfate, hydroxypropylmethylcellulose 2208, ethylcellulose and dibasic calcium phosphate,dihydrate in a suitable mixing bowl and blend under a nitrogen overlay.

[0154] 3. Granulate the blend from Step 2 with the solution fromStep. 1. pass the wet granulation through suitable milling equipment tobreakup large lumps.

[0155] 4. Dry the wet granulation at about 70° C. in a suitable fluidbed processor to a loss on drying between 0.5 to 2.0% as determined by amoisture balance or equivalent.

[0156] 5. Pass the dried granules through suitable milling equipment.

[0157] 6. Add the requisite amounts of silicon dioxide and magnesiumstearate to the dried, milled granules and blend.

[0158] 7. Compress the blend on a suitable tablet press.

[0159] The matrix cores are coated in the following manners:

[0160] A. Preparation of Coating Dispersions and Solutions

[0161] 1. First Film Coating Solution

[0162] (1) Disperse Simethicone and polyethylene glycol 8000 in aportion of purified water and agitate until completely dissolved.

[0163] (2) To the product of step 1, add the remainder of the purifiedwater and the talc; stir the so-formed suspension at room temperatureuntil homogeneous.

[0164] (3) Slowly add the so-formed homogeneous suspension of step 2 tothe stirred EUDRAGIT NE30D dispersion and continue to mix the so-formedmixture until a homogeneous dispersion is formed. Pass the dispersionthrough a screen.

[0165] (4) Spray the dispersion onto the matrix cores maintained at 40°C.±5° C. on a rotating pan.

[0166] (5) Dry the cooled matrix cores on the rotating pan.

[0167] 2. Second Film Coating Dispersion

[0168] (1) Disperse the Simethicone and polyethylene glycol 8000 in aportion of purified water. Add additional water and stir the dispersionat room temperature until completely dissolved.

[0169] (2) Slowly add desloratadine to the dispersion of step 1 and mixuntil a uniform dispersion is formed. Combine with the talc with theso-formed uniform dispersion, and continue agitation until a homogenoussuspension is formed.

[0170] (3) Add dispersion of step 2 to the EUDRAGIT NE 30D dispersionand mix until a uniform dispersion is formed. Pass the dispersionthrough a screen.

[0171] (4) Spray the requisite amount of the dispersion from step 3 ontothe matrix core with the first coating in a rotating pan at 25-27° C.

[0172] (5) Dry the coated matrix cores on the rotating pan.

[0173] 3. The Third Film Coating Solution

[0174] (1) Add the hydroypropyl methylcellulose 2910 to hot purifiedwater (75° C.) and agitate until a solution forms. Cool the so-formedsolution to room temperature.

[0175] (2) To a separate container, add Simethicone and polyethyleneglycol 8000 to purified water and continue to mix until a solution isformed.

[0176] (3) Add talc to solution of step 2 and continue to mix until auniform dispersion is formed.

[0177] (4) Add the solution of step 1 to the dispersion of step 3 andcontinue to mix until

[0178] (5) Add FD&C Blue No. 2 aluminum lake containing EDTA as achelating agent to purified water in a third container and

[0179] (6) Add the Blue lake solution of step 5 to the dispersion ofstep 4 and mix until a homogeneous mixture is formed.

[0180] (7) Slowly add the mixture of step 6 to a dispersion of EUDRAG ITNE30D and continue to mix until homogeneous.

[0181] (8) Pass dispersion of step 6 through 60 mesh screen.

[0182] (9) Spray the requisite amount of the dispersion of step 8 ontothe twice-coated matrix cores in a rotating pan at 35°-45° C. Dry thethrice-coated matrix cores in the form of tablets in rotating pan.

[0183] (10) Remove the so-formed tablets from pan and further dry at 40°for 16 hours.

EXAMPLE 2

[0184] The following more preferred composition of the present inventionwas made in accordance with the above procedure of Example 1. 1. MatrixCore Ingredient mg/core Pseudoephedrine Sulfate USP 240 HydroxypropylMethylcellulose 2208 USP 320 100,000 cps Ethylcellulose NF Type 7 80Dibasic Calcium Phosphate USP Dihydrate 108 Povidone USP 40 SiliconDioxide NF 8 Magnesium Stearate NF 4 Approximate Matrix Core Weight: 800mg 2. Matrix Core Coatings 1. First Film Coating: Ingredient mg/tabletSimethicone 0.22 Polyethylene glycol 8000 0.27 Talc NF 2.72 EthylAcrytalc/Methyl Methacrylate neutral copolymer 2.72 (30% dispersion inwater) Subtotal for first coating 5.93 mg 3. Second Film (ImmediateRelease) Coating mg/tablet Desloratadine 5.0 Simethicone 0.28Polyethylene glycol 8000 1.83 Talc NF 7.00 Ethyl Acrylate/Methylmethacrylate neutral copolymer 6.09 Subtotal for second coating 20.20 mg4. Third Film Coating mg/tablet Hydroxypropyl Methylcellulose 2910 USP 6cps 2.09 Talc NF 5.79 Ethyl Acrylate/Methyl Methacrylate Neutral 4.18copolymer Polyethylene Glycol 8000 NF 0.42 Simethicone 0.11 SpectraSpray Med Blue Dye 3.65 Subtotal for third coating: 16.24 mg ApproximateTotal of Three Coatings Weight: 42.37 mg Approximate Tablet (MatrixCore& Three Coatings) 842.97 mg Weight:

[0185] The in vitro dissolution profile of the tablet of Example 1 wasmeasured in a stirred 0.1N HCl solution at 37° C. (1^(st) hour) andthereafter in a stirred phosphate buffer having a pH of 7.5 at 37° C.The 80% of desloratadine in the coating was dissolved within the first45 minutes and the total dose of pseudoephedrine sulfate in the matrixcore was slowly released via erosion and dissolution mechanisms over aperiod of at least 16 hours.

Example 3

[0186] The following more preferred composition of the present inventionwas made in accordance with the above procedure of Example 1. 1. MatrixCore Ingredient mg/core Pseudoephedrine Sulfate USP 240 HydroxypropylMethylcellulose 2208 USP 320 100,000 cps Ethylcellulose NF Type 7 80Dibasic Calcium Phosphate USP Dihydrate 108 Povidone USP 40 SiliconDioxide NF 8 Magnesium Stearate NF 4 Approximate Matrix Core Weight: 800mg 2. Matrix Core Coatings 1. First Film Coating: Ingredient mg/tabletSimethicone 0.22 Polyethylene glycol 8000 0.27 Talc NF 2.72 EthylAcrytalc/Methyl Methacrylate neutral copolymer 2.72 (30% dispersion inwater) Subtotal for first coating 5.93 mg 2. Second Film (ImmediateRelease) Coating mg/tablet Desloratadine 6.0 Simethicone 0.28Polyethylene glycol 8000 1.83 Talc NF 5.88 Ethyl Acrylate/Methylmethacrylate neutral copolymer 6.09 Subtotal for second coating 20.08 mg3. Third Film Coating mg/tablet Hydroxypropyl Methylcellulose 2910 USP 6cps 2.09 Talc NF 5.79 Ethyl Acrylate/Methyl Methacrylate Neutral 4.18copolymer Polyethylene Glycol 8000 NF 0.42 Simethicone 0.11 SpectraSpray Med Blue Dye 3.65 Subtotal for third coating 16.24 ApproximateTotal of Three Coatings Weight: 42.37 mg Approximate Tablet (MatrixCoreand Three Coatings) 842.97 mg Weight:

EXAMPLE 4

[0187] The following more preferred composition of the present inventionwas made in accordance with the above procedure of Example 1. 1. MatrixCore Ingredient mg/core Pseudoephedrine Sulfate USP 240 HydroxypropylMethylcellulose 2208 USP 320 100,000 cps Ethylcellulose NF Type 7 80Dibasic Calcium Phosphate USP Dihydrate 108 Povidone USP 40 SiliconDioxide NF 8 Magnesium Stearate NF 4 Approximate Matrix Core Weight: 800mg Matrix Core Coatings 2. Matrix Core Coatings 1. First Film Coating:Ingredient mg/tablet Simethicone 0.22 Polyethylene glycol 8000 0.27 TalcNF 2.72 Ethyl Acrytalc/Methyl Methacrylate neutral copolymer 2.72 (30%dispersion in water) Subtotal for first coating 5.93 mg 2. Second Film(Immediate Release) Coating mg/tablet Desloratadine 5.0 Simethicone 0.28Polyethylene glycol 8000 0.61 Talc NF 5.17 Ethyl Acrylate/Methylmethacrylate neutral copolymer 6.09 Hydroxypropyl Methylcellulose 2910USP 6 cps 3.05 Subtotal for second coating 20.20 mg 3. Third FilmCoating mg/tablet Hydroxypropyl Methylcellulose 2910 USP 6 cps 2.09 TalcNF 5.79 Ethyl Acrylate/Methyl Methacrylate Neutral 4.18 copolymerPolyethylene Glycol 8000 NF 0.42 Simethicone 0.11 Spectra Spray Med BlueDye 3.65 Subtotal for third coating 16.24 mg Approximate Total of ThreeCoatings Weight: 42.37 mg Approximate Tablet (MatrixCore and ThreeCoatings) 842.37 mg Weight:

EXAMPLE 5

[0188] The following more preferred composition of the present inventionwas made in accordance with the above procedure of Example 1. Theformulation of Example 4 was used except in the second filmdesloratadine layer the amount of polyethylene glycol 8000 was increasedto 1.83 mg and the amount of talc was increased to 7.00 and no HPMC 2910USP 6 cps was added. 1. Matrix Core Ingredient mg/core PseudoephedrineSulfate USP 240 Hydroxypropyl Methylcellulose 2208 USP 320 100,000 cpsEthylcellulose NF Type 7 80 Dibasic Calcium Phosphate USP Dihydrate 108Povidone USP 40 Silicon Dioxide NF 8 Magnesium Stearate NF 4 ApproximateMatrix Core Weight: 800 mg Matrix Core Coatings 2. Matrix CoreCoatings 1. First Film Coating: Ingredient mg/tablet Simethicone 0.22Polyethylene glycol 8000 0.27 Talc NF 2.72 Ethyl Acrytalc/MethylMethacrylate neutral copolymer 2.72 (30% dispersion in water) Subtotalfor first coating 5.93 mg 2. Second Film (Immediate Release) Coatingmg/tablet Desloratadine 5.0 Simethicone 0.28 Polyethylene glycol 80001.83 Talc NF 7.00 Ethyl Acrylate/Methyl methacrylate neutral copolymer6.09 (30% dispersion in water) Subtotal for second coating 20.20 mg 3.Third Film Coating mg/tablet Hydroxypropyl Methylcellulose 2910 USP 6cps 2.09 Talc NF 5.79 Ethyl Acrylate/Methyl Methacrylate Neutral 4.18copolymer (30% dispersion in water) Polyethylene Glycol 8000 NF 0.42Simethicone 0.11 Spectra Spray Med Blue Dye 3.65 Subtotal for thirdcoating 16.24 mg Approximate Total of Three Coatings Weight: 42.37 mgApproximate Tablet (MatrixCore and Three Coatings) 842.37 mg Weight:

[0189] The total desloratadine degradation products in the film-coatedextended release solid oral dosage composition of Example 5 was 0.8weight percent after storage of the compositions at 25 C. and 60%relative humidity for at least about 24 months. The major desloratadinedegradation products are (1) N-methyl-desloratadine which was present ata level of about 0.3 weight percent, and (2) N-formyldesloratadine whichwas present at a level of about 0.4 weight percent.

[0190] Similar results would be expected if a decongestant effectiveamount of another pharmaceutically acceptable pseudoephedrine salt,e.g., pseudoephedrine hydrogen chloride was used in place ofpseudoephedrine sulfate.

[0191] The compositions of the present invention are useful fortreatment of allergic and/or inflammatory conditions of the skin (e.g.urticaria) and the upper and lower airway passages including the nasaland non-nasal symptoms of seasonal allergic rhinitis including nasalcongestion in patients in need of such treating. The precise dosage anddosage regimen may be varied by the attending clinician in view of theteachings herein depending upon the requirements of the patient, e.g.,the patient's age, sex and the severity of the allergic and/orinflammatory condition being treated. Determination of the proper dosageand dosage regimen for a particular patient will be within the skill ofthe attending clinician.

[0192] While we have hereinabove presented a number of preferredembodiments of this invention by way of example, it is apparent that thescope of the invention is to be defined by the scope of the appendedclaims.

[0193] The in vitro dissolution profile of the tablets of Examples 1-5were measured in a stirred 0.1N HCl solution at 37° C. (1^(st) hour) andthereafter in a stirred phosphate buffer having a pH of 7.5 at 37° C.For Example 5, The 91% of desloratadine in the immediate release layerwas dissolved within the first 30 minutes, 94% in 45 minutes and 95% ofdesloratadine was dissolved within 1 hr and the 92-95% of thepseudoephedrine sulfate in the sustained release layer was slowlyreleased via erosion and dissolution mechanisms over a period of atleast 16 hours (with 20% in 1 hr, 33% in 2 hrs. and 71% in 8 hrs, 79% in10 hrs, and 92-95% in 16 hrs).

[0194] Similar results would be expected if a decongestant effectiveamount of another pharmaceutically acceptable pseudoephedrine salt,e.g., pseudoephedrine hydrochloride was used in place of pseudoephedrinesulfate.

What is claimed is:
 1. A film-coated extended release solid oral dosagecomposition comprising (a) a core comprising an effective amount ofpseudoephedrine or pharmaceutically acceptable salt thereof, and (b) afilm coating uniformly covering the core and comprising an effectiveamount of desloratadine wherein the amount of pseudoephedrine orpharmaceutically acceptable salt thereof is effective to produce ageometric maximum plasma concentration of pseudoephedrine of about 345ng/mL to about 365 ng/mL at a time of about 7.60 hrs to about 8.40 hrsand the amount of desloratadine is effective to produce a geometricmaximum plasma concentration of desloratadine of about 2.10 ng/mL toabout 2.45 ng/mL at a time of about 4.0 hours to about 4.5 hours afteradministration of a single dose of said composition.
 2. The film-coatedextended release solid oral dosage composition of claim 1 wherein theamount of desloratadine is effective to produce a geometric maximumplasma concentration of 3-hydroxydesloratadine of about 0.75 ng/mL toabout 1.15 ng/mL at a time of about 5.50 hours to about 6.25 hours afteradministration of a single dose of said composition.
 3. The film-coatedextended release solid oral dosage composition of claim 1 wherein thecore is a matrix core and wherein there is a first film coatinguniformly covering the matrix core and a second film coating uniformlycovering the first coating comprising an effective amount ofdesloratadine. 4 The film-coated extended release solid oral dosagecomposition of claim 3 wherein (a.) the first film coating uniformlycovering the matrix core comprises (1) a water-swellable film-formingneutral or cationic co-polymeric ester; (2) a lubricant; (3) afilm-modifier; and optionally, (4) an anti-foaming agent; and wherein(b) the second film coating uniformly covering the first coatingcomprises: 1) an effective amount of desloratadine sufficient to producea geometric maximum plasma concentration of desloratadine of about 2.10ng/mL to about 2.45 ng/mL at a time of about 4.0 hours to about 4.5hours after administration of a single dose of said composition; 2) awater-swellable film-forming neutral or cationic co-polymeric ester; 3)a lubricant; 4) a water soluble film-modifier; and 5) optionally, ananti-foaming agent;
 5. The film-coated extended release solid oraldosage composition of claim 4 wherein the amount of desloratadine iseffective to produce a geometric maximum plasma concentration of3-hydroxydesloratadine of about 0.75 ng/mL to about 1.15 ng/mL at a timeof about 5.50 hours to about 6.25 hours after administration of a singledose of said composition.
 6. The film-coated extended release solid oraldosage composition of claim 4 which further comprises a third filmcoating uniformly coating the second film coating, said third coatingcomprising: 1 a pharmaceutically acceptable dye; 2 a water-swellablefilm-forming neutral or cationic copolymeric ester; 3 a lubricant; 4 atleast one water soluble film-modifier; and 5 optionally, an anti-foamingagent. 7 The film-coated extended release solid oral dosage compositionof claim 6 wherein the water-soluble film-modifyier is a low viscosityhydroxypropyl methylcellulose, hydroxyethyl methyl cellulose or sodiumcarboxymethyl cellulose or a a polyethylene glycol selected frompolyethylene glycol 200 to a polyethylene 8000, or mixtures thereof. 8.The film-coated extended release solid oral dosage composition of claim4 wherein the water-insoluble calcium, magnesium or aluminum salt in thematrix core is a carbonate, phosphate, silicate or sulfate of calcium,magnesium or aluminum or mixtures thereof.
 9. A film-coated extendedrelease solid oral dosage composition comprising (a) a core comprisingabout 240 mg of pseudoephedrine or pharmaceutically acceptable saltthereof, and (b) a film coating uniformly covering the core andcomprising about 5 mg of desloratadine wherein total desloratadinedegration products in the film-coated extended release oral dosagecomposition is less than or equal to about 2.0% .
 10. The film-coatedextended release solid oral dosage composition of claim 9 herein thetotal desloratadine degration products comprise less than or about 0.3to about 0.4% of N-methyldesloratadine, and less than or about 0.4 toabout 0.5% of N-formyldesloratadine.
 11. The film-coated extendedrelease solid oral dosage composition of claim 9 wherein totaldesloratadine degration products in the film-coated extended releaseoral dosage composition is less than or about 0.8 to about 1.0 weightpercent of the composition.
 12. The film-coated extended release solidoral dosage composition of claim 9 wherein total pseudoephedrinedegradation products in the film-coated extended release oral dosagecomposition is less than about 0.5 weight percent to no more than about1.1 weight percent of the composition.
 13. The film-coated extendedrelease oral dosage composition of claim 1 wherein the matrix corecomprises: Ingredient mg/core Pseudoephedrine Sulfate about 120 to about360 Hydroxypropyl Methylcellulose about 160 to about 480 2208, 100,000cps Ethylcellulose about 40 to about 120 Dibasic Calcium PhosphateDihydrate about 56 to about 162 Povidone about 20 to about 60 SiliconDioxide about 6 to about 12 Magnesium Stearate about 2 to about 6 MatrixCore Weight Range: about 400 to about 1200 mg


14. The film-coated extended release oral dosage composition of claim 4wherein the first film coating comprises: (1) a neutral copolymer ofethyl acrylate and methyl acrylate; (2) a lubricant selected from talc,silicon, polyethylene glycol 200 to polyethylene 8000; (3) apolyethylene glycol selected from polyethylene glycol 200 topolyethylene glycol 8000; and (4) optionally a pharmaceuticallyacceptable mixture of homologous liquid methyl siloxane polymers andsilica gel.
 15. The film-coated extended release oral dosage compositionof claim 4 wherein the second film coating comprises: (1) an amount ofdesloratadine effective to produce a geometric maximum plasmaconcentration of desloratadine of about 2.10 ng/mL to about 2.45 ng/mLat a time of about 4.0 hours to about 4.5 hours after administration ofa single dose of said composition; (2) a neutral copolymer of ethylacrylate and methyl acrylate; (3) a lubricant selected from talc,silicon dioxide and magnesium stearate; (4) a polyethylene glycolselected from polyethylene glycol 200 to a polyethylene glycol 8000; and(5) optionally, a pharmaceutically acceptable mixture of homologousliquid methyl siloxane polymers and silica gel.
 16. The film-coatedextended release oral dosage composition of claim 2 wherein the thirdfilm coating comprises: (1) a neutral copolymer of ethyl acrylate andmethyl acrylate; (2) a lubricant selected from talc, silicon dioxide andmagnesium stearate; (3) an effective amount of a water-solublefilm-modifying agent is a low viscosity hydroxypropyl methylcellulose,hydroxyethyl methylcellulose or sodium carboxymethyl cellulose, or a apolyethylene glycol selected from polyethylene glycol 200 to apolyethylene glycol 8000, or mixtures thereof; (4) a pharmaceuticallyacceptable dye; and (5) optionally, a pharmaceutically acceptablemixture of homologous liquid methyl siloxane polymers and silica gel. 17A film-coated extended release solid oral dosage composition comprising(a) a core comprising about 240 of pseudoephedrine or pharmaceuticallyacceptable salt thereof, and (b) a first film coating uniformly coveringthe core; and (c) a second film coating uniformly covering the firstcoating comprising about 5 mg of desloratadine; wherein more than about90% of the desloratadine in solid oral dosage composition dissolves intoa stirred 0.1N HCl solution at 37° C. in about 45 minutes, and more thanabout 90% of the pseudoephedrine sulfate in solid oral dosagecomposition dissolves into a stirred 0.1N HCl solution at 37° C. (1^(st)hour) and thereafter in a stirred phosphate buffer having a pH of 7.5 at37° C. over 16 hours.
 18. A film-coated extended release solid oraldosage composition comprising (a) a core comprising an effective amountof pseudoephedrine or pharmaceutically acceptable salt thereof, and (b)a film coating uniformly covering the core and comprising an effectiveamount of desloratadine wherein the amount of pseudoephedrine orpharmaceutically acceptable salt thereof is effective to produce ageometric mean steady state maximum plasma concentration ofpseudoephedrine of about 382 ng/mL to about 664 ng/mL at a time of about5.25 hrs to about 7.99 hrs after administration of a daily dose of saidcomposition for at least about 10 consecutive days and the amount ofdesloratadine is effective to produce a geometric mean steady statemaximum plasma concentration of desloratadine of about about 1.59 ng/mLto about 3.39 ng/mL at a time of about about 2.24 hours to about 5.12hours after administration of a daily dose of said composition for atleast about 12 consecutive days.
 19. A film-coated extended releasesolid oral dosage composition of claim 18 wherein the geometric meansteady state maximum plasma concentration of pseudoephedrine is about418 ng/mL to about 628 ng/mL at a time of about 5.32 hrs to about 7.98hrs after administration of a daily dose of said composition for atleast about 10 consecutive days and the geometric mean steady statemaximum plasma concentration of desloratadine is about about 1.95 ng/mLto about 2.93 ng/mL at a time of about 2.94 hours to about 4.42 hoursafter administration of a daily dose of said composition for at leastabout 12 consecutive days.
 20. The film-coated extended release solidoral dosage composition of claim 18 wherein the amount of desloratadineis effective to produce a geometric mean steady state maximum plasmaconcentration of 3-hydroxy-desloratadine of about 1.25 ng/mL to about1.87 ng/mL at a time of about 3.44 hours to about 5.86 hours and ageometric mean steady state value for the area under the plasmaconcentration-time curve from 0-24 hours for 3-hydroxy-desloratadine wasabout 20.3 ng hr/mL to about 3.11 ng hr/mL after administration of adaily dose of said composition for at least about 12 consecutive days21. The film-coated extended release solid oral dosage composition ofclaim 18 wherein the geometric mean steady state value for the areaunder the plasma concentration-time curve from 0 to 24 hours fordesloratadine was about 23.0 ng hr/mL to about 46.6 ng hr/mL.
 22. Thefilm-coated extended release solid oral dosage composition of claim 18wherein the geometric mean steady state value for the area under theplasma concentration-time curve from 0 to 24 hours for desloratadine wasabout 27.8 ng hr/mL to about 41.8 ng hr/mL.
 23. The film-coated extendedrelease solid oral dosage composition of claim 18 wherein the geometricmean steady state value for the area under the plasma concentration-timecurve from 0 to 24 hours for pseudoephedrine was about 6244 ng hr/mL toabout 11346 ng hr/mL.
 24. The film-coated extended release solid oraldosage composition of claim 18 wherein the geometric mean steady statevalue for the area under the plasma concentration-time curve from 0 to24 hours for pseudoephedrine was about 7030 ng hr/mL to about 10554 nghr/mL.
 25. A film-coated extended release solid oral dosage compositioncomprising (a) a core comprising an effective amount of pseudoephedrineor pharmaceutically acceptable salt thereof, and (b) a film coatinguniformly covering the core and comprising an effective amount ofdesloratadine, wherein the amount of pseudoephedrine or pharmaceuticallyacceptable salt thereof is effective to produce a geometric mean steadystate minimum plasma concentration of pseudoephedrine of about 82 ng/mLto about 243 ng/mL after administration of a daily dose of saidcomposition for at least about 10 consecutive days and the amount ofdesloratadine is effective to produce a geometric mean steady stateminimum plasma concentration of desloratadine of about 0.307 ng/mL toabout 1.095 ng/mL after administration of a daily dose of saidcomposition for at least about 12 consecutive days.
 26. The film-coatedextended release solid oral dosage composition of claim 25 wherein thegeometric mean steady state minimum plasma concentration ofpseudoephedrine is about 129 ng/mL to about 193 ng/mL afteradministration of a daily dose of said composition for at least about 10consecutive days and the geometric mean steady state minimum plasmaconcentration of desloratadine is about 0.624 ng/mL to about 0.946 ng/mLafter administration of a daily dose of said composition for at leastabout 12 consecutive days.
 27. The film-coated extended release solidoral dosage composition of claim 25 wherein the amount of desloratadineis effective to produce a geometric mean steady state miniimum plasmaconcentration of 3-hydroxy-desloratadine of about 0.503 ng/mL to about0.875 ng/mL after administration of a daily dose of said composition forat least about 12 consecutive days. 28 The film-coated extended releasesolid oral dosage composition of claim 25 wherein the amount ofdesloratadine is effective to produce a geometric mean steady stateminiimum plasma concentration of 3-hydroxy-desloratadine of about 0.551ng/mL to about 0.827 ng/mL after administration of a daily dose of saidcomposition for at least about 12 consecutive days 29) A method oftreating allergic and inflammatory conditions of the upper and lowerairway passages and skin which comprises administering to a patient inneed of such treating an effective amount of the film-coated extendedrelease solid composition of claim
 1. 30) A method of treating nasalcongestion associated with allergic and inflammatory conditions of theupper and lower airway passages and skin which comprises administeringto a patient in need of such treating an effective amount of thefilm-coated extended release solid composition of claim
 1. 31) A methodof treating urticaria which comprises administering to a patient in needof such treating an effective amount of the film-coated extended releasesolid composition of claim
 1. 32) A method of treating the nasal andnon-nasal symptoms of perennial and seasonal allergic rhinitis whichcomprises administering to a patient in need of such treating aneffective amount of the film-coated extended release solid compositionof claim 1.